2. Adjuvant Therapy for HER2+ Breast Cancer Dana-Farber Cancer Institute
Eric P. Winer, MD
Dana-Farber Cancer Institute
Boston, MA
August

3. First-Generation Adjuvant Trastuzumab Trials

4. Overall Survival Joint Analysis of AC-T +/- Trastuzumab
Perez et al, JCO 2014

5. Disease Events in Joint Analysis (with extended follow-up)
AC-T (n=2018)
AC-TH (n=2028)
First Event
680
473
Local Recurrence
119 82
Distant Recurrence
416
241
Contralateral 29 13
Other malignancy 74 66
Death w/o disease 31 38
Perez et al, JCO 2014

6. BCIRG-006 DFS Final Analysis (10.3yrs)
74.6%
Trastuzumab-containing regimens remain superior at 10y follow-up
No formal comparison of anthracycline containing vs not
Despite benefits of trastuzumab, 25% of patients have events before 10 years – still room for improvement
In years rather then months ?
Slamon et al, SABCS 2015

7. Optimal Duration of Trastuzumab
HERA: No benefit of 2 years vs 1 year
PHARE: 6 months marginally worse than 1 year
SHORT HER Trial: Non-inferiority of shorter duration could not be established
CONCLUSION: 1 year is standard

8. ALTTO Trial: DFS Analysis No added benefit from Lapatinib
MFU = 4.5 yrs * **
* 97.5% CI
Piccart et al, JCO 2016
**p-value ≤ required for statistical significance

9. APHINITY: Trial Design
Chemotherapy* + trastuzumab + placebo
Chemotherapy* + trastuzumab + pertuzumab
Randomisation and treatment
within 8 weeks of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks)
(concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
Central confirmation of HER2 status
(N = 4805) F O L W - U P 10 Y E A R S
S U R G E R Y
*A number of standard anthracycline or non-anthracycline (TCH) regimens were allowed

10. APHINITY: Key Eligibility Criteria
Inclusion Criteria
Exclusion Criteria
HER2-positive status confirmed by a central review (IHC 3+ or FISH-/CISH-positive)*
Node-positive, any tumour size except T0
Node-negative
Tumour size >1 cm OR
For tumours >0.5 and ≤1 cm, at least 1 of:
histological/nuclear grade 3
ER- and PR-negative
age <35
Baseline LVEF ≥55%
Prior invasive breast cancer
Non-operable breast cancer
Metastatic disease (stage IV)
Previous non-breast malignancies (except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin)
Previous or current anti-cancer therapy or previous radiotherapy for any malignancy
Cardiac dysfunction or serious medical conditions
* Wolff A et al, J Clin Oncol 2013

11. APHINITY: Summary of first occurrence of an IDFS event
Majority of occurrences were distant, visceral
Placebo
Pertuzumab
n=2400
Total patients with IDFS event, n (%)
171 (7.1)
210 (8.7)
Category of first IDFS event, n (%)
Distant recurrence
Locoregional recurrence
Contralateral breast cancer
Death without prior event
112 (4.7)
26 (1.1)
5 (0.2)
28 (1.2)
139 (5.8)
34 (1.4)
11 (0.5)
All patients with a distant recurrence at any time during the study, n (%)
119 (5.0)
145 (6.0)
Site of first distant recurrence n (%)
Lung/liver/pleural effusion
CNS
Other
Bone
43 (1.8)
46 (1.9)
9 (0.4)
21 (0.9)
61 (2.5)
45 (1.9)
30 (1.2)
Patients who experience additional iDFS event(s) within 61 days of their 1st iDFS event are reported in the category according to the following hierarchy: [1] Distant recurrence; [2] Locoregional recurrence; [3] Contralateral breast cancer; [4] Death without prior event.

12. APHINITY (Intent-to-Treat) Invasive Disease Free Survival Analysis

13. APHINITY: Subgroup Analyses
No. of Patients / No. of Events
3-year IDFS Rate, %
Interaction test p-value
Subgroup
Pertuzumab
Placebo
Hazard Ratio (95%CI)
All patients
171 / 2400
210 / 2404
0.82 (0.67–1.00)
94.1
93.2 NA
Nodal status
0 positive nodes, tumor ≤1cm
2 / 90
4 / 84
0.48 (0.09–2.60)
97.7
97.5
0.374
0 positive nodes, tumor >1cm
30 / 807
25 / 818
1.23 (0.72–2.10)
98.5
1–3 positive nodes
55 / 907
75 / 900
0.73 (0.52–1.04)
94.9
93.8
≥4 positive nodes
84 / 596
106 / 602
0.79 (0.59–1.05)
87.5
84.7
0 positive nodes
32 / 897
29 / 902
1.13 (0.68–1.86)
98.4
0.169
≥1 positive nodes
139 / 1503
181 / 1502
0.77 (0.62–0.96)
92.0
90.2
Adjuvant chemotherapy regimen
Anthracycline
139 / 1865
171 / 1877
0.82 (0.66–1.03)
93.0
0.996
Non-anthracycline
32 / 535
39 / 527
0.82 (0.51–1.31)
94.0
Central hormone receptor status
Positive (ER- and/or PgR-positive)
100 / 1536
119 / 1546
0.86 (0.66–1.13)
94.8
94.4
0.543
Negative (ER- and PgR-negative)
71 / 864
91 / 858
0.76 (0.56–1.04)
92.8
91.2
Protocol version
Protocol A
120 / 1828
143 / 1827
0.84 (0.66–1.08)
94.7
0.686
Protocol Amendment B
51 / 572
67 / 577
0.77 (0.53–1.11)
91.9
90.6
Menopausal status at screening
Pre-menopausal
93 / 1152
96 / 1173
0.99 (0.75–1.32)
93.5
93.7
0.069
Post-menopausal
78 / 1242
113 / 1220
0.68 (0.51–0.91)
94.5
92.7
Age group (years)
<40
30 / 326
32 / 327
0.96 (0.59–1.59)
93.4
93.1
0.781
40–49
48 / 708
53 / 702
0.89 (0.60–1.32)
94.3
50–64
69 / 1051
91 / 1082
0.78 (0.57–1.07)
93.3
≥65
24 / 315
34 / 293
0.70 (0.41–1.17)
92.9
Tumor size (cm)
<2
41 / 977
64 / 944
0.62 (0.42–0.92)
97.0
94.6
0.203
2–<5
108 / 1273
115 / 1283
0.96 (0.74–1.24)
92.5 ≥5
22 / 147
31 / 174
0.85 (0.49–1.47)
Sex
Female
171 / 2397
209 / 2396
0.82 (0.67–1.01)
No. of Events / No. of Patients
Unstratified
1/5
1/2 1 2 5
Pertuzumab better
Placebo better

14. APHINITY: Node-positive Subgroup

15. APHINITY: Node-negative Subgroup

16. APHINITY: Hormone Receptor-negative Subgroup

17. APHINITY: Hormone Receptor-positive Subgroup

18. APHINITY: Cardiac Endpoints
Pertuzumab
n=2364
Treatment difference ptz vs. pla (95% CI)
N (%)
Primary cardiac endpoint
17 (0.7)
0.4 (0.0, 0.8)
8 (0.3)
Heart failure NYHA III/IV + LVEF drop*
Cardiac death**
15 (0.6)
2 (0.08)
6 (0.2)
Recovered according to LVEF 7 4
Secondary cardiac endpoint
Asymptomatic or mildly symptomatic LVEF drop*
64 (2.7)
-0.1 (-1.0, 0.9)
67 (2.8)
*LVEF drop = ejection fraction drop ≥10% from baseline AND to below 50%

19. APHINITY: Common Grade > 3 Adverse Events
Pertuzumab
n=2364
Placebo
n=2405
Neutropenia
385 (16.3%)
377 (15.7%)
Febrile Neutropenia
287 (12.1%)
266 (11.1%)
Neutrophil count decreased
228 ( 9.6%)
230 ( 9.6%)
Diarrhoea
232 (9.8%)
90 ( 3.7%)
Anaemia
163 ( 6.9%)
113 ( 4.7%)

20. When Should We Use Pertuzumab?
High risk disease
ER negative
Node positive (All patients? -- different criteria for ER+ and ER-)
Avoid in node negative
Will have to monitor results over time
Still no survival advantage, and ultimately likely to be small

21. Can We Improve in the Adjuvant HER2+ Setting? ExteNet: Study Design
2-year follow-up for iDFS
5-year follow-up for iDFS
5 + year survival
Part A
Part B
Part C
HER2+ breast cancer (local)
Prior adjuvant trastuzumab & chemotherapy
Lymph node –/+ or residual invasive disease after neoadjuvant therapy
ER/PR + or –
N=2880
Neratinib x 1 year
240mg/day
1:1 randomization
Placebo x 1 year
A sizeable minority still experience recurrences in spite of chemotherapy plus trastuzumab.
HERA did not support longer duration Trastuzumab.
Primary endpoint: invasive disease-free survival (iDFS) at 2 years (4 years after treatment completion)
Complicated study with many amendments

22. Adjuvant Extended Neratinib: Improvement in DFS with Greater in ER+
Chan et al, Lancet Oncology 2016

23. What is the role for adjuvant neratinib?
FDA approved extented neratinib
No evidence of benefit with pertuzumab
Therapy extends for one year, and is not without toxicity
Will it be used, and if so, in whom?
Possible role in VERY high risk patients, perhaps those with very high risk ER+ disease, and perhaps in those who do not respond to neoadjuvant antibody-based therapy

24. What About Stage I HER2+ Tumors?

25. Risk in < 1cm Node-Negative HER2+ Tumors
* endocrine therapy permitted
About 15% risk of relapse in small node-negative tumors in most worrisome dataset
Gonzalez-Angulo, JCO 2009
Increased risk in T1b/T1c HER2+ cancers
Given lower risk, and significant benefits of trastuzumab, a less intensive chemotherapy regimen may be most appropriate

26. Background
Retrospective data suggests that patients with small HER2+ breast cancer have more than just a minimal risk of disease recurrence
Majority of pivotal adjuvant trials excluded these patients
APT was designed to address treatment for this patient population
Presented by: Sara M. Tolaney

27. FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)*
APT Trial Study Design
Enroll T P T P T P T P T P T P T P T P T P T P T P T P
HER2+
ER+ or ER-
Node Negative
< 3 cm
PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12
Accrual N=406
Less than 20% had T1a
50% had T1c or T2 T T T T T T T T T T T T T
We conducted a single-arm, multi-center, investigator-initiated phase II trial of paclitaxel and trastuzumab in patients with node-negative tumors less than or equal to 3 cm
Essentially this treatment regimen is the adjuvant ACTH regimen without the AC.
Treatment consisted of 80 mg/m2 IV weekly for 12 weeks in combination with weekly IV trastuzumab for a total of 12 doses. After completion of 12 weeks of paclitaxel, the dosing of trastuzumab could be continued on a weekly basis or changed to 6 mg per kilogram IV every 3 weeks for 40 weeks to complete a full year of trastuzumab therapy.
Patients treated with lumpectomy were required to receive adjuvant radiation therapy. Whole-breast radiotherapy was initiated after completion of the paclitaxel and partial breast radiation was performed prior to initiation of protocol therapy. Trastuzumab treatment was continued during radiotherapy. Women with HR+ tumors, were recommended to start adjuvant hormonal therapy after completion of paclitaxel.
FOLLOWED BY 13 EVERY 3 WEEK DOSES
OF TRASTUZUMAB (6 mg/kg)*
*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks
** Radiation and hormonal therapy was initiated after completion of paclitaxel
Tolaney et al, NEJM 2015

28. Enrollment Allocation Follow-Up
Assessed for eligibility (n=410)
Excluded (n=4)
Not meeting inclusion criteria (n=1)
Declined to participate (n=3)
Allocated to intervention (n=406)
Did not receive intervention (n=0))
Allocation
Discontinued intervention (n=50)
Protocol specified toxicity (n=24)
Toxicity not protocol-specified (n=6)
Intercurrent illness (n=1)
Patient decision (n=13)
Physician decision (n=4)
Disease recurrence (n=1)
Unknown reason (n=1)
Discontinued follow-up (n=69)
Death (n=14)
Withdrew from study (n=22)
Lost to follow up (n=20)
Patients did not consent to f/u beyond 5 yrs (n=13)
Analyzed (n=406)
Follow-Up

29. Patient Characteristics%
Age
<50
50-70
≥70
132
233 41 33 57 10
Size of Primary Tumor
T1a ≤0.5 cm
T1b >0.5-≤1.0
T1c >1.0-≤2.0
T2 >2.0-≤3.0 77
124
169 36 19 31 42 9
Histologic Grade
I Well differentiated
II Moderately differentiated
III Poorly differentiated 44
131
228 11 32 56
HR Status (ER and/or PR)
Positive
Negative
272
134 67

30. Disease-Free Survival Events
DFS Event
N (%)
Time to event
[months; mean(range)]
Any recurrence or death
23 (5.7)
Local/Regional Recurrence*
Ipsilateral axilla (HER2+)
Ipsilateral breast (HER2+)
5 (1.2) 3 2
29 (12-54)
51 (37-65)
New Contralateral Primary Breast Cancer
HER2+
HER2-
Unknown
6 (1.5) 1 56
36 (12-59)
87 (84-90)
Distant Recurrence
4 (1.0)
49 (27-63)
Death
Non-breast cancer related
8 (2.0)
58 (13-71)

31. Disease-Free Survival
Point Est.
95% Conf. Interval
No. of events
3-yr DFS
98.5%
97.2% to 99.7% 6
5-yr DFS
96.3%
94.4% to 98.2% 14
7-yr DFS
93.3%
90.4% to 96.2% 23

32. Recurrence Free Interval
Point Est.
95% Conf. Interval
No. of events
3-yr RFI
99.2%
98.4% to >99.9% 3
5-yr RFI
98.1%
96.8% to 99.5% 7
7-yr RFI
97.5%
95.9% to 99.1% 9

33. Overall Survival Point Est. 95% Conf. Interval No. of events 99.7%
3-yr OS
99.7%
99.2% to >99.9% 1
5-yr OS
98.7%
97.5% to 99.8% 5
7-yr OS
95.0%
92.4% to 97.7% 14

34. Causes of Deaths DFS Events (n) Stroke (1) Ovarian Cancer (1)
Dementia (1)
Suicide (1)
Unknown cause without known recurrence (4)
Other events counted in OS
Osteosarcoma
Chronic Obstructive Pulmonary Disease
Lung Cancer
Triple-negative breast cancer (2)
HER2-positive breast cancer (1)

35. Cardiac Safety of Trastuzumab without Anthracycline: APT Trial
Most had stable LVEF during treatment
3.2% had asymptomatic drop in LVEF requiring trastuzumab hold
0.5% had grade 3 LV dysfunction, with risk factors for cardiac dysfunction
Dang et al, JAMA Oncol 2016

36. APT Trial Summary
With a median follow-up of 6.5 years, the 7-yr DFS was 93.3%, with just 4 distant recurrences
The 7-yr RFI (including invasive local/regional + distant recurrences + deaths due to breast cancer) was 97.5%
Trend towards fewer recurrences in the HR+ patients (7 yr DFS: 94.6% vs 90.7%)
Adjuvant TH is now a standard regimen for the majority of patients with stage I HER2+ breast cancer

37. Netherlands Population Registry for stage 1, HER2+ breast cancers
Van Ramshort et al. SABCS 2015

38. Netherlands Observational Study
of Small HER2+ Tumors
OS BCSS
Van Ramshort et al. SABCS 2015

39. R 3 1 ATEMPT Trial Schema Trastuzumab-DM1 q3weeks X17 Stage I HER2+*
ER+ or ER-
PS 0-1
Adequate organ fx
N=375 R
Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 1
N=500
N=125
*HER2-positive defined as IHC 3+ or FISH≥2.0; will be confirmed by central HER2 testing prior to study enrollment
Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy
Adjuvant radiation therapy can be administered concurrently with study treatment.
PI: Sara Tolaney, MD, MPH

40. Adjuvant Therapy For HER2+ Tumors <2 cm
< 1 mm cm cm cm
YES!
YES!
ER-
SELECTIVELY
YES!
MAYBE,
BUT NOT
IN EVERYONE
GENERALLY
NOT
ER+
If chemotherapy to be used, would be comfortable
giving paclitaxel/trastuzumab to any of these patients

41. The Challenge of HER2 Testing
Often relatively straightforward, but confusion can arise from:
Testing variability (pre/post testing)
Biologic heterogeneity (probably the major issue)
Clinical HER2 positivity
FISH > 2.0
IHC 3+
HER2 gene copy number > 6
Oncotype Dx should not be used to assess HER2
Requires close collaboration with pathology and selective retesting
We still don’t have anything close to a perfect measure for “HER2-driven”
Two equivocal results do not
equal one positive result! 41

42. Future Directions More For Some, Less For Others
As biologic therapy improves, we should be able to back off on some and occasionally all chemotherapy
Will selected patients be able to receive antibody therapy alone?
Will others be able to receive hormonal therapy plus anti-Her2 therapy?
Narrow role for Neratinib will be defined
Watch for role of CDK 4/6 inhibitors in Her2+ disease in the years ahead

43. Standard Approaches Stage I -- majority can be treated with TH only
Stage II/III – AC-T with H+/-P or TCH+/-P
Pertuzumab appropriate for node positive ER- disease and ER+ in setting of multiple positive nodes
Adjuvant and neoadjuvant largely interchangeable for many patients, though neoadjuvant has some distinct advantages
Role of neratinib uncertain